This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Our lab is focused on the study of virus nucleocapsid structure. We are interested in how structure is involved with assembly and function of negative strand RNA viruses (NSRVs). The group of NSRVs includes some of the most dangerous human pathogens, such as Ebola, rabies, avian influenza, and measles viruses. This proposal is an extension of our previous and continued work with the viral nucleocapsid (N) protein of vesicular stomatitis virus (VSV). The decameric structure of N complexed with a 90-mer of RNA has been completed. Now, complexes between the N-RNA and other VSV proteins are the focus of study. Additionally, we are continuing to expand beyond the Rhabdovirus family, to study nucleocapsid proteins of three other NSRV families, Orthomyxoviridae, Paramyxoviridae and Bunyaviridae (influenza virus, RSV and Bunyamwera virus, respectively). The structural study of the influenza nucleoprotein (NP) is complimented with the design of inhibitors against the viral glycoprotein HA. We have found a novel class of fusion inhibitors that have a potent and irreversible inhibitory effect on influenza viruses. We also continue the study of HIV CA/inhibitor complexes. These inhibitors are designed disrupt viral assembly and maturation. Here we look to transform initial hits into optimized drug leads and ultimately into second generation drug candidates.